Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Nat Commun. 2017 Nov 22;8(1):1707. doi: 10.1038/s41467-017-01645-7.

Abstract

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Azepines / pharmacology
  • Cachexia / genetics
  • Cachexia / metabolism
  • Cachexia / prevention & control*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression Regulation
  • Humans
  • Interleukin-6 / metabolism
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Mice
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / prevention & control
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / therapy*
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Azepines
  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Interleukin-6
  • Nuclear Proteins
  • Transcription Factors
  • Triazoles
  • interleukin-6, mouse
  • AMP-Activated Protein Kinases